tbuckley/cabot-search huggingface dataset:
Single-cell RNA sequencing distinctly characterizes the wide heterogeneity in pediatric mixed phenotype acute leukemia
Authors: Hope L. Mumme, Sunil S. Raikar, Swati S. Bhasin, Beena E. Thomas, Taylor Lawrence, Elizabeth P. Weinzierl, Yakun Pang, Deborah DeRyckere, Chuck Gawad, Daniel S. Wechsler, Christopher C. Porter, Sharon M. Castellino, Douglas K. Graham, Manoj Bhasin
Journal: Genome Medicine (2023)

Abstract Background Mixed phenotype acute leukemia (MPAL), a rare subgroup of leukemia characterized by blast cells with myeloid and lymphoid lineage features, is difficult to diagnose and treat. A better characterization of MPAL is essential to understand the subtype heterogeneity and how it compares with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Therefore, we performed single-cell RNA sequencing (scRNAseq) on pediatric MPAL bone marrow (BM) samples to develop a granular map of the MPAL blasts and microenvironment landscape. Methods We analyzed over 40,000 cells from nine pediatric MPAL BM samples to generate a single-cell transcriptomic landscape of B/myeloid (B/My) and T/myeloid (T/My) MPAL. Cells were clustered using unsupervised single-cell methods, and malignant blast and immune clusters were annotated. Differential expression analysis was performed to identify B/My and T/My MPAL blast-specific signatures by comparing transcriptome profiles of MPAL with normal BM, AML, and ALL. Gene set enrichment analysis (GSEA) was performed, and significantly enriched pathways were compared in MPAL subtypes. Results B/My and T/My MPAL blasts displayed distinct blast signatures. Transcriptomic analysis revealed that B/My MPAL profile overlaps with B-ALL and AML samples. Similarly, T/My MPAL exhibited overlap with T-ALL and AML samples. Genes overexpressed in both MPAL subtypes’ blast cells compared to AML, ALL, and healthy BM included MAP2K2 and CD81 . Subtype-specific genes included HBEGF for B/My and PTEN for T/My. These marker sets segregated bulk RNA-seq AML, ALL, and MPAL samples based on expression profiles. Analysis comparing T/My MPAL to ETP, near-ETP, and non-ETP T-ALL, showed that T/My MPAL had greater overlap with ETP-ALL cases. Comparisons among MPAL subtypes between adult and pediatric samples showed analogous transcriptomic landscapes of corresponding subtypes. Transcriptomic differences were observed in the MPAL samples based on response to induction chemotherapy, including selective upregulation of the IL-16 pathway in relapsed samples. Conclusions We have for the first time described the single-cell transcriptomic landscape of pediatric MPAL and demonstrated that B/My and T/My MPAL have distinct scRNAseq profiles from each other, AML, and ALL. Differences in transcriptomic profiles were seen based on response to therapy, but larger studies will be needed to validate these findings.
Author Correction: Single-nucleus genomics in outbred rats with divergent cocaine addiction-like behaviors reveals changes in amygdala GABAergic inhibition
Authors: Jessica L. Zhou, Giordano de Guglielmo, Aaron J. Ho, Marsida Kallupi, Narayan Pokhrel, Hai-Ri Li, Apurva S. Chitre, Daniel Munro, Pejman Mohammadi, Lieselot L. G. Carrette, Olivier George, Abraham A. Palmer, Graham McVicker, Francesca Telese
Journal: Nature Neuroscience (2023)
Unfolded protein response in gastric glandulocytes of rats with the pharmacological correction of type 2 diabetes
Authors: Y.G. Klys, T.R. Kerimov, S.I. Savosko, Y.S. Osadchuk, S.M. Smirnov, L.V. Natrus
Journal: GASTROENTEROLOGY (2023)

Background. The cellular and molecular mechanisms underlying gastrointestinal complications caused by type 2 diabetes mellitus (T2DM) may involve accumulation of misfolded proteins in the endoplasmic reticulum that disrupts protein homeostasis and activates a signaling pathway termed the unfolded protein response (UPR). The goal of the present study was to assess the state of the UPR system in gastric glandulocytes of untreated and metformin- and propionate-treated T2DM rats. Materials and methods. Rats with induced T2DM received metformin, propionate, and their combination. Analysis of the levels of 78-kDa glucose-regulated protein (GRP78), activating transcription factor 6 (ATF6), protein kinase R-like endoplasmic reticulum kinase (PERK), and inositol-requiring enzyme 1 (IRE1) was performed by Western blotting and immunohistochemical assessment of slices. Results. In T2DM rats, an increase in GRP78 vs. control (normal) group was found. Metformin and propionate treatment led to an increase in GRP78; under combination therapy, its content was registered at the level in untreated T2DM group. An increase in the ATF6 in T2DM rats was found, and all treatment regimens contributed to its growth. The PERK level in T2DM rats exceeded that in controls, and propionate treatment caused its decrease to the level observed in control group. An immunohistochemical assessment revealed a tendency to increase the intensity of immunoreaction for GRP78 in T2DM rats. With metformin treatment, an intensive immunoreaction for GRP78 was revealed. The general trend in T2DM rats was a significant increase in ATF6 expression. Conclusions. Combination treatment with metformin and propionate led to a significant decrease in GRP78, which may indicate a positive effect of such therapy. New data on propionic acid effect on UPR in the stomach have been obtained that may be beneficial for developing possible treatment strategies in complications of gastropathy caused by diabetes.
The level of pancreatic fecal elastase-1 and the risk of cardiovascular complications in patients with chronic pancreatitis combined with arterial hypertension
Authors: A.Yu. Filippova, V.V. Kryvoshei
Journal: GASTROENTEROLOGY (2023)

Background. Chronic pancreatitis and malnutrition are associated with cardiovascular diseases and cardiovascular events, while the role of exocrine pancreatic insufficiency as a risk factor for cardiovascular events is unknown. The purpose of the study was to evaluate the level of pancreatic fecal elastase-1 in patients with chronic pancreatitis combined with hypertension and to determine the relationship with cardiovascular risk. Materials and methods. One hundred and ten patients (46 men, 64 women) aged 45–65 years with chronic pancreatitis were included in the study. The first group consisted of people with a combined course of chronic pancreatitis and hypertension; the second — with chronic pancreatitis alone. The levels of total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and very low-density cholesterol, pancreatic fecal elastase-1, total protein, serum content of albumin, iron, vitamin D, zinc and magnesium were evaluated in all patients. Results. In the group 1, there were significantly more cases of severe exocrine pancreatic insufficiency and a significantly lower number of patients with a normal level of pancreatic fecal elastase-1 (p &lt; 0.05). In addition, a very high cardiovascular risk was detected significantly more often in this group — 11.5 % (p &lt; 0.05). The main cardiovascular risk factors among patients with chronic pancreatitis, in addition to hypertension, included obesity and increased body weight — 70.9 % of cases. Elevated levels of TG, LDL, and total cholesterol were observed in 86.4, 94.5, and 91.8 % of patients with chronic pancreatitis combined with hypertension, respectively, and a reduced content of HDL-C was found in 34.5 % (p &lt; 0.05). Significantly higher levels of TG, LDL-C, total cholesterol, and a lower level of HDL were revealed in the group 1 compared to the group 2 (p &lt; 0.05). In patients of the group 1, a reliable inverse correlation was found between the pancreatic fecal elastase-1 and TG, atherogenic index, the SCORE2 scale (r = –0.43, p &lt; 0.05; r = –0.52, p &lt; 0.05; r = –0.48, p &lt; 0.05, respectively), as well as a reliable direct correlation with HDL level (r = 0.50; p &lt; 0.05). Conclusions. The combined course of chronic pancreatitis with exocrine pancreatic insufficiency and hypertension is associated with an increased cardiovascular risk. A decrease in the level of pancreatic fecal elastase-1 and malnutrition may be associated with an increase in the frequency of dyslipidemia and in the risk of cardiovascular events among these patients.
The value of osteopontin in predicting fibrosis in patients with chronic viral hepatitis C
Authors: A.G. Sheiko, K.V. Yurko
Journal: GASTROENTEROLOGY (2023)

Background. Diagnosis of an asymptomatic course of chronic viral hepatitis C (HCV) and the existing development of the fibrotic process by determining the marker capabilities of biochemical blood parameters (primarily osteopontin — OP) is an urgent issue in modern medicine. Purpose: to evaluate the prognostic value of biochemical blood markers for diagnosing an asymptoma­tic course of HCV and the existing fibrotic process. Materials and me­thods. Seventy-eight people were examined: 47 from the main group — 19 (40.4 %) women and 28 (59.6 %) men with chronic HCV, and 31 controls — 17 (54.8 %) women and 14 (45.2 %) men without chronic HCV. The median, as well as 25.0% and 75.0% quartiles and relative values were calculated for quantitative and qualitative measures, respectively. Predictors were determined using logistic regression analysis. Results. The data obtained by a univariate analysis indicate a significantly increased risk of develo­ping liver fibrosis on the background of chronic HCV, with alanine aminotransferase (ALT) levels increased by 1.037 times, aspartate aminotransferase (AST) by 1.051 times, gamma-glutamyl transferase (GGT) by 1.017 times; thymol turbidity test by 1.424 times; total protein by 1.162 times and OP by 3.002 times. With increased levels of triglycerides and very low-density lipoproteins, a significant decrease in these risks was found, by 74.7 and 94.7 %, respectively. A multivariate analysis found significantly increased risks of deve­loping liver fibrosis on the background of chronic HCV, with higher levels of AST, total protein, and OP (by 1.028, 1.195 and 2.510 times, respectively). Conclusions. With a significant liver damage by a fibrotic process (stage 3–4), as compared to stage 0–2, there is a probable predominance of biochemical liver markers in the blood of patients with HCV: ALT, AST, GGT, total protein and OP. AST, total protein, and OP were identified as reliable predictors of liver fibrosis. The developed mathematical model has high sensitivity and specificity: 87.5 and 83.9 %, respectively.
Clinical significance of serum levels of Saccharomyces cerevisiae IgA, IgG and perinuclear antineutrophil cytoplasmic antibodies in the differential diagnosis of inflammatory bowel diseases
Authors: Yu.M. Stepanov, M.V. Stoikevich, Yu.A. Gaydar, I.A. Klenina, O.M. Tatarchuk
Journal: GASTROENTEROLOGY (2023)

Background. It is important to search for biological markers with high specificity and sensitivity as a non-invasive method for accurate diagnosis of inflammatory bowel disease (IBD), in particular, differentiation of ulcerative colitis (UC) and Crohn’s disease (CD), which is important for both prognosis and treatment. The purpose of the study was to determine the titer of anti-Saccharomyces cerevisiae antibodies (ASCA) IgG, IgA, perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and their clinical significance in patients with ulcerative colitis and Crohn’s disease. Materials and methods. The study included 49 patients with IBD who were treated at the Department of Intestinal Di­seases of the State Institution “Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine”. All patients were divided into two groups: 33 individuals with UC and 16 with CD. In addition, the patients were divided into groups depending on the severity of UC course: mild — 3, moderate — 26, and 4 individuals had severe UC. Among patients with CD, severity was moderate in 13 cases and severe CD was detected in 3 cases. p-ANCA IgG were determined by an indirect immunofluorescence assay. The serum level of ASCA IgA and IgG was evaluated by the enzyme-linked immunosorbent assay. The results were statistically processed using the Statistica 6.1 software package. Results. Most patients with UC appeared to have p-ANCA, and in patients with CD, an increased level of ASCA IgA and IgG was found. Among patients with CD, the level of ASCA IgA and IgG depended on the severity of the disease, which was confirmed by the revealed correlation between their level and the severity of the disease (r = 0.608; p = 0.012). Analysis showed that the p-ANCA IgG test for confirming the diagnosis of UC has a sensitivity of 63 % and a specificity of 86 %, whereas the presence of an elevated level of ASCA IgA or IgG for the diagnosis of CD has a sensitivity of 72 % and a specificity of 82 %. The combination of positive p-ANCA IgG and negative ASCA IgA, IgG in patients with UC showed a sensitivity and specificity of 75.6 and 68.8 %, respectively, with a diagnostic accuracy of 68.8 %. For combination of positive ASCA IgA, IgG and negative p-ANCA IgG in patients with CD, the sensitivity was 81.3 % and the specificity was 80 % with a diagnostic accuracy of 80.8 %. Therefore, the simultaneous determination of ASCA IgA, IgG and p-ANCA IgG increases the positive predictive accuracy in the differential diagnosis of UC and CD among patients with IBD. Conclusions. It was found that the separate assessment of ASCA IgA, IgG and p-ANCA IgG for the differentiation of UC and CD has lower sensitivity and specificity, but when the two tests are combined, the predictive value of a positive result and specificity can be significantly increased.
Effects of visceral obesity on cytokine and hormonal regulation in patients with gastroesophageal reflux disease
Authors: Yu.M. Stepanov, L.M. Mosiychuk, O.M. Tatarchuk, O.M. Shevtsova, O.P. Petishko
Journal: GASTROENTEROLOGY (2023)

Background. In recent years, pathogenetic mechanisms underlying the association of gastroesophageal reflux disease (GERD) and metabolic syndrome have caused considerable interest among researchers. The purpose is to determine the features of cytokine balance, carbohydrate metabolism, leptin and ghrelin levels depending on the amount of visceral fat in patients with GERD. Materials and methods. Fifty-six patients with GERD were examined. According to the results of bioimpedance analysis, they were divided into the groups: 23 patients with a dangerous and 33 with a safe amount of visceral fat. The levels of tumor necrosis factor α, interleukin-6, interleukin-10, ghrelin and leptin were determined in the blood serum of all patients by the enzyme immunoassay method. Also, the levels of glucose, insulin were determined and the insulin resistance index (HOMA-IR) was calculated in patients with GERD. Results. In the group of GERD patients with a dangerous amount of visceral fat, an increase in the concentration of the pro-inflammatory cytokine interleukin-6 by 12 % was found with a simultaneous decrease in the level of the anti-inflammatory cytokine interleukin-10 by 22 % (p &lt; 0.05), an increase in the HOMA-IR median by 1.3 times (p &lt; 0.05) compared to the patients with a safe amount of visceral fat. The median level of ghrelin in patients with a dangerous visceral fat amount increased significantly, by 2.0 times (p &lt; 0.05) compared to the control group. Correlation analysis showed an association between visceral fat and leptin (r = 0.37; p = 0.0008), interleukin-10 (r = –0.28; p = 0.0116), insulin (r = 0.41; p = 0.001), HOMA-IR (r = 0.48; p = 0.00001). Conclusions. In GERD patients, an increase in the amount of visceral fat was associated with a violation of the cytokine balance, carbohydrate metabolism, increased level of ghrelin. The determined statistically significant correlation between the amount of visceral fat and the level of leptin indicates a functional relationship between the body composition according to bioimpedance analysis and the hormonal activity of adipose tissue in patients with GERD.
The relationship between zonulin level and indicators of carbohydrate metabolism in patients with metabolic-associated fatty liver disease combined with type 2 diabetes mellitus
Authors: O.K. Didyk, V.V. Chernyavskyi, V.P. Shypulin
Journal: GASTROENTEROLOGY (2023)

Background. The purpose of the study was to determine the relationship between serum zonulin level and indicators of carbohydrate metabolism in patients with metabolic-associated fatty liver disease (MAFLD) combined with type 2 diabetes mellitus (DM). Materials and methods. The study involved 78 patients with MAFLD and type 2 DM, who were examined and divided into 2 groups. The first group consisted of 42 patients with МAFLD and type 2 DM without small intestinal bacterial overgrowth (SIBO). The second group included 36 patients with МAFLD and type 2 DM in combination with SIBO. The control group consisted of 20 practically healthy persons. The content of serum zonulin was determined by the enzyme-linked immunosorbent assay (ELISA) using the IDK Zonulin ELISA test systems, KR5601 (Immundiagnostik AG, Germany). Results. The study of the content of serum zonulin revealed its significant increase in patients with MAFLD combined with type 2 DM without SIBO — (70.78 ± 2.09) ng/ml and with SIBO — (82.64 ± 2.71) ng/ml compared to the control group — (13.26 ± 1.53) ng/ml (p &lt; 0.001). When comparing the parameters of carbohydrate metabolism, a significant increase was found in fasting blood glucose — (10.25 ± 0.30) mmol/l and (10.43 ± 0.33) mmol/l, insulin — (22.66 ± 0.64 mU/l) and (22.96 ± 0.70) mU/l, НOMA-IR — 10.4 ± 0.4 and 10.87 ± 0.66, HbA1c — 8.89 (8.03–9.95) % and 8.61 (8.02–10.34) %, C-peptide — (5.44 ± 0.06) ng/ml and (5.95 ± 0.10) ng/ml in patients with MAFLD combined with type 2 diabetes without and with SIBO, respectively, as compared to the control group (p &lt; 0.001). Indicators of fasting plasma glucose, insulin, HbA1c and the НOMA-IR in patients of the first and second groups did not differ significantly (p &gt; 0.05), and the level of C-peptide was increased significantly in patients of the second group compared to the first one (p &lt; 0.001). Correlation analysis between serum zonulin level and indicators of carbohydrate metabolism in patients with MAFLD combined with type 2 DM without and with SIBO found a moderate positive correlation with levels of glucose, insulin and HOMA-IR, and a weak correlation was found between serum zonulin level with HbA1c and C-peptide. Conclusions. An increase in serum zonulin was found in patients with MAFLD combined with type 2 DM without and with SIBO, which indicated an increase in the intestinal permeability. The content of serum zonulin was associated with hyperglycemia and hyperinsulinemia. Thus, impaired intestinal permeability is pathogenetically associated with the development of insulin resistance.
Liver structure and fibrosis markers in modeling alcohol-induced liver injury and correction of detected disorders
Authors: V.I. Didenko, I.A. Klenina, O.I. Hrabovska, Yu.A. Gaidar, O.O. Halinskyi, V.A. Karachynova, D.F. Mylostуva
Journal: GASTROENTEROLOGY (2023)

Background. Chronic alcohol use leads to alcoholic liver fibrosis. Today, a sufficient number of scientific studies are focused on the pathometabolic mechanisms of liver fibrosis development and formation in animal models. The purpose of our study was to investigate structural changes and liver stiffness, biochemical markers of fibrosis in rats with chronic alcoholic liver injury (CALI) modeling and to evaluate the changes of these parame­ters with different types of treatment. Materials and methods. Eighty-nine rats were divided into experimental groups depending on the duration of alcohol exposure (4 and 12 weeks) and the corresponding type of correction (metadoxine and prebiotic). Results. When modeling CALI at week 4, morphological studies revealed moderate large-droplet fatty hepatosis and mild fibrosis in the central venule of the liver lobes. After 12 weeks of forced alcoholization, with more pronounced general intoxication, hepatocytes have dystrophic changes such as appearance of single or grouped dystrophic cells in the parenchyma. A combination of protein and fatty dystrophy was more common. Elastography allowed to detect structural changes in the liver at the early stages of fibrosis formation when modeling CALI for 12 weeks. There were also changes in the levels of biochemical parameters: free and protein-bound hydroxyproline, glycosaminoglycans. According to the results of elastography, liver stiffness in rats increased maximally after prebiotic correction in all approaches compared to the controls. After correction of CALI, both early- and long-term, fibrosis markers normalized in rat liver homogenate after administration of metadoxine and prebiotic. After prebiotic correction at week 12 of alcoholization, we observed a 12% decrease in liver parenchymal stiffness in the CALI modeling group and a 19% decrease (p &lt; 0.05) in the placebo group. After correction with metadoxine, there was a 1.5-fold increase in free hydroxyproline levels in rat liver homogenate at week 12 and a 1.2-fold increase in glycosaminoglycans (p &lt; 0.05) at week 4 compared to the CALI modeling group. Conclusions. Long-term alcoholization of animals led to the development of dystrophic changes in hepatocytes, protein and fatty degeneration, and an increase in the number of capillaries. Against this background, liver stiffness and biochemical parameters changed. After correction with metadoxine and prebiotic, changes in the liver stiffness and fibrosis markers were observed at week 12 of CALI modeling.
MalariaSED: a deep learning framework to decipher the regulatory contributions of noncoding variants in malaria parasites
Authors: Chengqi Wang, Yibo Dong, Chang Li, Jenna Oberstaller, Min Zhang, Justin Gibbons, Camilla Valente Pires, Mianli Xiao, Lei Zhu, Rays H. Y. Jiang, Kami Kim, Jun Miao, Thomas D. Otto, Liwang Cui, John H. Adams, Xiaoming Liu
Journal: Genome biology (2023)

Malaria remains one of the deadliest infectious diseases. Transcriptional regulation effects of noncoding variants in this unusual genome of malaria parasites remain elusive. We developed a sequence-based, ab initio deep learning framework, MalariaSED, for predicting chromatin profiles in malaria parasites. The MalariaSED performance was validated by published ChIP-qPCR and TF motifs results. Applying MalariaSED to ~ 1.3 million variants shows that geographically differentiated noncoding variants are associated with parasite invasion and drug resistance. Further analysis reveals chromatin accessibility changes at Plasmodium falciparum rings are partly associated with artemisinin resistance. MalariaSED illuminates the potential functional roles of noncoding variants in malaria parasites.